scholarly journals PHLPP1 Counter-regulates STAT1-mediated Inflammatory Signaling

2019 ◽  
Author(s):  
Ksenya Cohen-Katsenelson ◽  
Joshua D. Stender ◽  
Agnieszka T. Kawashima ◽  
Gema Lordén ◽  
Satoshi Uchiyama ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Target Genes ◽  
Cytokine Signaling ◽  
List Type ◽  
Ph Domain ◽  
Inflammatory Signaling ◽  
Lps Challenge ◽  
Localization Signal

ABSTRACTInflammation is an essential aspect of innate immunity but also contributes to diverse human diseases. Although much is known about the kinases that control inflammatory signaling, less is known about the opposing phosphatases. Here we report that deletion of the gene encoding PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) protects mice from lethal lipopolysaccharide (LPS) challenge and liveEscherichia coliinfection. Investigation of PHLPP1 function in macrophages reveals that it controls the magnitude and duration of inflammatory signaling by dephosphorylating the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce the expression of target genes involved in innate immunity and cytokine signaling. This previously undescribed function of PHLPP1 depends on a bipartite nuclear localization signal in its unique N-terminal extension. Our data support a model in which nuclear PHLPP1 dephosphorylates STAT1 to control the magnitude and duration of inflammatory signaling in macrophages.HIGHLIGHTSPHLPP1 controls the transcription of genes involved in inflammatory signalingPHLPP1 dephosphorylates STAT1 on Ser727 to reduce its transcriptional activityPHLPP1 has a nuclear localization signal and a nuclear exclusion signalLoss of PHLPP1 protects mice from sepsis-induced death

scholarly journals PHLPP1 counter-regulates STAT1-mediated inflammatory signaling

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Ksenya Cohen Katsenelson ◽  
Joshua D Stender ◽  
Agnieszka T Kawashima ◽  
Gema Lordén ◽  
Satoshi Uchiyama ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Target Genes ◽  
Cytokine Signaling ◽  
Ph Domain ◽  
Inflammatory Signaling ◽  
Gene Encoding ◽  
Lps Challenge ◽  
Escherichia Coli Infection ◽  
Localization Signal ◽  
Leucine Rich Repeat Protein

Inflammation is an essential aspect of innate immunity but also contributes to diverse human diseases. Although much is known about the kinases that control inflammatory signaling, less is known about the opposing phosphatases. Here we report that deletion of the gene encoding PH domain Leucine-rich repeat Protein Phosphatase 1 (PHLPP1) protects mice from lethal lipopolysaccharide (LPS) challenge and live Escherichia coli infection. Investigation of PHLPP1 function in macrophages reveals that it controls the magnitude and duration of inflammatory signaling by dephosphorylating the transcription factor STAT1 on Ser727 to inhibit its activity, reduce its promoter residency, and reduce the expression of target genes involved in innate immunity and cytokine signaling. This previously undescribed function of PHLPP1 depends on a bipartite nuclear localization signal in its unique N-terminal extension. Our data support a model in which nuclear PHLPP1 dephosphorylates STAT1 to control the magnitude and duration of inflammatory signaling in macrophages.

Identification of a nuclear localization signal in suppressor of cytokine signaling 1

2008 ◽  
Vol 22 (12) ◽  
pp. 4296-4305 ◽  
Author(s):  
Andrea Baetz ◽  
Christian Koelsche ◽  
Julia Strebovsky ◽  
Klaus Heeg ◽  
Alexander H. Dalpke
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Localization Signal

scholarly journals Reactivation of Epstein–Barr virus can be triggered by an Rta protein mutated at the nuclear localization signal

2005 ◽  
Vol 86 (2) ◽  
pp. 317-322 ◽  
Author(s):  
Tsuey-Ying Hsu ◽  
Yao Chang ◽  
Pei-Wen Wang ◽  
Mei-Ying Liu ◽  
Mei-Ru Chen ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Epstein Barr Virus ◽  
Target Genes ◽  
Ectopic Expression ◽  
Epithelial Cell Line ◽  
Barr Virus ◽  
Early Protein ◽  
Localization Signal ◽  
Epstein Barr

Rta, an immediate-early protein of Epstein–Barr virus (EBV), is a transcriptional activator that induces lytic gene expression and triggers virus reactivation. Being located predominantly in the nucleus, Rta can exert its transactivation function through either direct DNA binding or certain indirect mechanisms mediated by cellular signalling and other transcriptional factors. This study examined whether the subcellular localization of Rta was critical for the induction of target genes. First, 410KRKK413 was identified as a nuclear localization signal (NLS) of Rta. An Rta mutant with the NLS converted to 410AAAA413 showed cytoplasmic localization and failed to activate the promoter of BGLF5. Interestingly, ectopic expression of the Rta mutant still disrupted EBV latency in an epithelial cell line. Reporter gene assays revealed that the NLS-mutated Rta retained the ability to activate two lytic promoters, Zp and Rp, at a considerable level. Thus, the cytoplasmic Rta mutant could induce expression of endogenous Zta and Rta, triggering reactivation of EBV.

scholarly journals Coordinate Nuclear Targeting of the FANCD2 and FANCI Proteins via a FANCD2 Nuclear Localization Signal

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e81387 ◽  
Author(s):  
Rebecca A. Boisvert ◽  
Meghan A. Rego ◽  
Paul A. Azzinaro ◽  
Maurizio Mauro ◽  
Niall G. Howlett
Keyword(s):  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Nuclear Targeting ◽  
Localization Signal
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